tbuckley/cabot-search huggingface dataset:
In utero delivery of mRNA to the heart, diaphragm and muscle with lipid nanoparticles
Authors: Kewa Gao, Jie Li, Hengyue Song, Hesong Han, Yongheng Wang, Boyan Yin, Diana L. Farmer, Niren Murthy, Aijun Wang
Journal: Bioactive Materials (2023)

Nanoparticle-based drug delivery systems have the potential to revolutionize medicine, but their low vascular permeability and rapid clearance by phagocytic cells have limited their medical impact. Nanoparticles delivered at the in utero stage can overcome these key limitations due to the high rate of angiogenesis and cell division in fetal tissue and the under-developed immune system. However, very little is known about nanoparticle drug delivery at the fetal stage of development. In this report, using Ai9 CRE reporter mice, we demonstrate that lipid nanoparticle (LNP) mRNA complexes can deliver mRNA in utero, and can access and transfect major organs, such as the heart, the liver, kidneys, lungs and the gastrointestinal tract with remarkable efficiency and low toxicity. In addition, at 4 weeks after birth, we demonstrate that 50.99 ± 5.05%, 36.62 ± 3.42% and 23.7 ± 3.21% of myofiber in the diaphragm, heart and skeletal muscle, respectively, were transfected. Finally, we show here that Cas9 mRNA and sgRNA complexed to LNPs were able to edit the fetal organs in utero. These experiments demonstrate the possibility of non-viral delivery of mRNA to organs outside of the liver in utero, which provides a promising strategy for treating a wide variety of devastating diseases before birth.
Long-term outcomes of pouch surveillance and risk of neoplasia in familial adenomatous polyposis
Authors: Roshani V. Patel, Kit Curtius, Ripple Man, Jordan Fletcher, Victoria Cuthill, Susan K. Clark, Alexander C. von Roon, Andrew Latchford
Journal: Endoscopy (2023)

Abstract Background Long-term pouch surveillance outcomes for familial adenomatous polyposis (FAP) are unknown. We aimed to quantify surveillance outcomes and to determine which of selected possible predictive factors are associated with pouch dysplasia. Methods Retrospective analysis of collected data on 249 patients was performed, analyzing potential risk factors for the development of adenomas or advanced lesions ( ≥ 10 mm/high grade dysplasia (HGD)/cancer) in the pouch body and cuff using Cox proportional hazards models. Kaplan–Meier analyses included landmark time-point analyses at 10 years after surgery to predict the future risk of advanced lesions. Results Of 249 patients, 76 % developed at least one pouch body adenoma, with 16 % developing an advanced pouch body lesion; 18 % developed an advanced cuff lesion. Kaplan–Meier analysis showed a 10-year lag before most advanced lesions developed; cumulative incidence of 2.8 % and 6.4 % at 10 years in the pouch body and cuff, respectively. Landmark analysis suggested the presence of adenomas prior to the 10-year point was associated with subsequent development of advanced lesions in the pouch body (hazard ratio [HR] 4.8, 95 %CI 1.6–14.1; P = 0.004) and cuff (HR 6.8, 95 %CI 2.5–18.3; P &lt; 0.001). There were two HGD and four cancer cases in the cuff and one pouch body cancer; all cases of cancer/HGD that had prior surveillance were preceded by ≥ 10-mm adenomas. Conclusions Pouch adenoma progression is slow and most advanced lesions occur after 10 years. HGD and cancer were rare events. Pouch phenotype in the first decade is associated with the future risk of developing advanced lesions and may guide personalized surveillance beyond 10 years.
A Trem2R47H mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques
Authors: Kristine M. Tran, Shimako Kawauchi, Enikö A. Kramár, Narges Rezaie, Heidi Yahan Liang, Jasmine S. Sakr, Angela Gomez-Arboledas, Miguel A. Arreola, Celia da Cunha, Jimmy Phan, Shuling Wang, Sherilyn Collins, Amber Walker, Kai-Xuan Shi, Jonathan Neumann, Ghassan Filimban, Zechuan Shi, Giedre Milinkeviciute, Dominic I. Javonillo, Katelynn Tran, Magdalena Gantuz, Stefania Forner, Vivek Swarup, Andrea J. Tenner, Frank M. LaFerla, Marcelo A. Wood, Ali Mortazavi, Grant R. MacGregor, Kim N. Green
Journal: Molecular Neurodegeneration (2023)

Abstract Background The TREM2 R47H variant is one of the strongest genetic risk factors for late-onset Alzheimer’s Disease (AD). Unfortunately, many current Trem2 R47H mouse models are associated with cryptic mRNA splicing of the mutant allele that produces a confounding reduction in protein product. To overcome this issue, we developed the Trem2 R47H NSS ( N ormal S plice S ite) mouse model in which the Trem2 allele is expressed at a similar level to the wild-type Trem2 allele without evidence of cryptic splicing products. Methods Trem2 R47H NSS mice were treated with the demyelinating agent cuprizone, or crossed with the 5xFAD mouse model of amyloidosis, to explore the impact of the TREM2 R47H variant on inflammatory responses to demyelination, plaque development, and the brain’s response to plaques. Results Trem2 R47H NSS mice display an appropriate inflammatory response to cuprizone challenge, and do not recapitulate the null allele in terms of impeded inflammatory responses to demyelination. Utilizing the 5xFAD mouse model, we report age- and disease-dependent changes in Trem2 R47H NSS mice in response to development of AD-like pathology. At an early (4-month-old) disease stage, hemizygous 5xFAD/homozygous Trem2 R47H NSS (5xFAD/ Trem2 R47H NSS ) mice have reduced size and number of microglia that display impaired interaction with plaques compared to microglia in age-matched 5xFAD hemizygous controls. This is associated with a suppressed inflammatory response but increased dystrophic neurites and axonal damage as measured by plasma neurofilament light chain (NfL) level. Homozygosity for Trem2 R47H NSS suppressed LTP deficits and loss of presynaptic puncta caused by the 5xFAD transgene array in 4-month-old mice. At a more advanced (12-month-old) disease stage 5xFAD/ Trem2 R47H NSS mice no longer display impaired plaque-microglia interaction or suppressed inflammatory gene expression, although NfL levels remain elevated, and a unique interferon-related gene expression signature is seen. Twelve-month old Trem2 R47H NSS mice also display LTP deficits and postsynaptic loss. Conclusions The Trem2 R47H NSS mouse is a valuable model that can be used to investigate age-dependent effects of the AD-risk R47H mutation on TREM2 and microglial function including its effects on plaque development, microglial-plaque interaction, production of a unique interferon signature and associated tissue damage.
Engineering Multifunctional Polyether Ether Ketone Implant: Mechanics‐Adaptability, Biominerialization, Immunoregulation, Anti‐Infection, Osteointegration, and Osteogenesis
Authors: Hongyun Ma, Hao Han, Xiaoming Zhao, Junping Ma, Xiaoyan Qu, Xiaoxiao Lou, Angxiu Suonan, Bo Lei, Yingang Zhang
Journal: Advanced Healthcare Materials (2023)

Abstract Polyether ether ketone (PEEK) has become one of the most promising polymer implants in bone orthopedics, due to the biocompatibility, good processability, and radiation resistance. However, the poor mechanics‐adaptability/osteointegration/osteogenesis/antiinfection limits the long‐term in vivo applications of PEEK implants. Herein, a multifunctional PEEK implant (PEEK‐PDA‐BGNs) is constructed through in situ surface deposition of polydopamine‐bioactive glass nanoparticles (PDA‐BGNs). PEEK‐PDA‐BGNs exhibit good performance on osteointegration and osteogenesis in vitro and in vivo, due to their multifunctional properties including mechanics‐adaptability, biominerialization, immunoregulation, anti‐infection, and osteoinductive activity. PEEK‐PDA‐BGNs can show the bone tissue‐adaptable mechanic surface and induce the rapid biomineralization (apatite formation) under a simulated body solution. Additionally, PEEK‐PDA‐BGNs can induce the M2 phenotype polarization of macrophages, reduce the expression of inflammatory factors, promote the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), and improve the osseointegration and osteogenesis ability of the PEEK implant. PEEK‐PDA‐BGNs also show good photothermal antibacterial activity and can kill 99% of Escherichia coli ( E. coli ) and Methicillin‐resistant Staphylococcus aureus (MRSA), suggesting their potential antiinfection ability. This work suggests that PDA‐BGNs coating is probably a facile strategy to construct multifunctional (biomineralization, antibacterial, immunoregulation) implants for bone tissue replacement.
CXCL8/CXCR2 signaling mediates bone marrow fibrosis and represents a therapeutic target in myelofibrosis
Authors: Andrew Dunbar, Dongjoo Kim, Min Lu, Mirko Farina, Robert L. Bowman, Julie L. Yang, Young C. Park, Abdul Karzai, Wenbin Xiao, Zach Zaroogian, Kavi O'Connor, Shoron Mowla, Francesca Gobbo, Paola Verachi, Fabrizio Martelli, Giuseppe Sarli, Lijuan Xia, Nada Elmansy, Maria Kleppe, Zhuo Chen, Yang Xiao, Erin M McGovern, Jenna Snyder, Aishwarya Krishnan, Corinne E. Hill, Keith Bryan Cordner, Anouar Zouak, Mohamed E. Salama, Jayden Yohai, Eric Tucker, Jonathan J Chen, Jing Zhou, Timothy S McConnell, Anna Rita Migliaccio, Richard Patrick Koche, Raajit K. Rampal, Rong Fan, Ross L Levine, Ronald Hoffman
Journal: Blood (2023)
<i>In vivo</i> HSC prime editing rescues Sickle Cell Disease in a mouse model
Authors: Chang Li, Aphrodite Georgakopoulou, Gregory A Newby, Peter J Chen, Kelcee A Everette, Kiriaki Paschoudi, Efthimia Vlachaki, Sucheol Gil, Anna K Anderson, Theodore Koob, Lishan Huang, Hongjie Wang, Hans-Peter Kiem, David R Liu, Evangelia Yannaki, André Lieber
Journal: Blood (2023)

Sickle Cell Disease (SCD) is a monogenic disease caused by a nucleotide mutation in the β-globin gene. Current gene therapy studies are mainly focused on lentivirus vector-mediated gene addition or CRISPR/Cas9-mediated fetal globin reactivation, leaving the root cause unfixed. We developed a vectorized prime editing system that can directly repair the SCD mutation in hematopoietic stem cells (HSCs) in vivo in a SCD mouse model (CD46/Townes mice). Our approach involved a single intravenous injection of a non-integrating, prime editor-expressing virus vector into mobilized CD46/Townes mice and low-dose drug selection in vivo. This procedure resulted in the correction of ~40% of bS alleles in HSCs. On average 43% of HbS was replaced by HbA thereby greatly mitigating the SCD phenotypes. Transplantation in secondary recipients demonstrated that long-term repopulating HSCs were edited. Highly efficient target site editing was achieved with minimal generation of insertions and deletions and no detectable off-target editing. Because of its simplicity and portability, our in vivo prime editing approach has the potential for application in resource-poor countries where SCD is prevalent.
Initiation of Continuous Glucose Monitoring Is Linked to Improved Glycemic Control and Fewer Clinical Events in Type 1 and Type 2 Diabetes in the Veterans Health Administration
Authors: Peter D. Reaven, Michelle Newell, Salvador Rivas, Xinkai Zhou, Gregory J. Norman, Jin J. Zhou
Journal: Diabetes Care (2023)

OBJECTIVE To determine the benefit of starting continuous glucose monitoring (CGM) in adult-onset type 1 diabetes (T1D) and type 2 diabetes (T2D) with regard to longer-term glucose control and serious clinical events. RESEARCH DESIGN AND METHODS A retrospective observational cohort study within the Veterans Affairs Health Care System was used to compare glucose control and hypoglycemia- or hyperglycemia-related admission to an emergency room or hospital and all-cause hospitalization between propensity score overlap weighted initiators of CGM and nonusers over 12 months. RESULTS CGM users receiving insulin (n = 5,015 with T1D and n = 15,706 with T2D) and similar numbers of nonusers were identified from 1 January 2015 to 31 December 2020. Declines in HbA1c were significantly greater in CGM users with T1D (−0.26%; 95% CI −0.33, −0.19%) and T2D (−0.35%; 95% CI −0.40, −0.31%) than in nonusers at 12 months. Percentages of patients achieving HbA1c &amp;lt;8 and &amp;lt;9% after 12 months were greater in CGM users. In T1D, CGM initiation was associated with significantly reduced risk of hypoglycemia (hazard ratio [HR] 0.69; 95% CI 0.48, 0.98) and all-cause hospitalization (HR 0.75; 95% CI 0.63, 0.90). In patients with T2D, there was a reduction in risk of hyperglycemia in CGM users (HR 0.87; 95% CI 0.77, 0.99) and all-cause hospitalization (HR 0.89; 95% CI 0.83, 0.97). Several subgroups (based on baseline age, HbA1c, hypoglycemic risk, or follow-up CGM use) had even greater responses. CONCLUSIONS In a large national cohort, initiation of CGM was associated with sustained improvement in HbA1c in patients with later-onset T1D and patients with T2D using insulin. This was accompanied by a clear pattern of reduced risk of admission to an emergency room or hospital for hypoglycemia or hyperglycemia and of all-cause hospitalization.
Effects of Semaglutide on Albuminuria and Kidney Function in People With Overweight or Obesity With or Without Type 2 Diabetes: Exploratory Analysis From the STEP 1, 2, and 3 Trials
Authors: Hiddo J.L. Heerspink, Ellen Apperloo, Melanie Davies, Dror Dicker, Kristian Kandler, Julio Rosenstock, Rasmus Sørrig, Jack Lawson, Niels Zeuthen, David Cherney
Journal: Diabetes Care (2023)

OBJECTIVE These post hoc analyses of the Semaglutide Treatment Effect in People with obesity (STEP) 1–3 trials (NCT03548935, NCT03552757, and NCT03611582) explored the effects of semaglutide (up to 2.4 mg) on kidney function. RESEARCH DESIGN AND METHODS STEP 1–3 included adults with overweight/obesity; STEP 2 patients also had type 2 diabetes. Participants received once-weekly subcutaneous semaglutide 1.0 mg (STEP 2 only), 2.4 mg, or placebo for 68 weeks, plus lifestyle intervention (STEP 1 and 2) or intensive behavioral therapy (STEP 3). Changes in urine albumin-to-creatinine ratio (UACR) and UACR status from baseline to week 68 were assessed for STEP 2. Changes in estimated glomerular filtration rate (eGFR) were assessed from pooled STEP 1–3 data. RESULTS In STEP 2, 1,205 (99.6% total cohort) patients had UACR data; geometric mean baseline UACR was 13.7, 12.5, and 13.2 mg/g with semaglutide 1.0 mg, 2.4 mg, and placebo, respectively. At week 68, UACR changes were −14.8% and −20.6% with semaglutide 1.0 mg and 2.4 mg, respectively, and +18.3% with placebo (between-group differences [95% CI] vs. placebo: −28.0% [−37.3, −17.3], P &amp;lt; 0.0001 for semaglutide 1.0 mg; −32.9% [−41.6, −23.0], P = 0.003 for semaglutide 2.4 mg). UACR status improved in greater proportions of patients with semaglutide 1.0 mg and 2.4 mg versus placebo (P = 0.0004 and P = 0.0014, respectively). In the pooled STEP 1–3 analyses, 3,379 participants had eGFR data; there was no difference between semaglutide 2.4 mg and placebo in eGFR trajectories at week 68. CONCLUSIONS Semaglutide improved UACR in adults with overweight/obesity and type 2 diabetes. In participants with normal kidney function, semaglutide did not have an effect on eGFR decline.
Noninvasive Hypoglycemia Detection in People With Diabetes Using Smartwatch Data
Authors: Vera Lehmann, Simon Föll, Martin Maritsch, Eva van Weenen, Mathias Kraus, Sophie Lagger, Katja Odermatt, Caroline Albrecht, Elgar Fleisch, Thomas Zueger, Felix Wortmann, Christoph Stettler
Journal: Diabetes Care (2023)

To develop a noninvasive hypoglycemia detection approach using smartwatch data.We prospectively collected data from two wrist-worn wearables (Garmin vivoactive 4S, Empatica E4) and continuous glucose monitoring values in adults with diabetes on insulin treatment. Using these data, we developed a machine learning (ML) approach to detect hypoglycemia (<3.9 mmol/L) noninvasively in unseen individuals and solely based on wearable data.Twenty-two individuals were included in the final analysis (age 54.5 ± 15.2 years, HbA1c 6.9 ± 0.6%, 16 males). Hypoglycemia was detected with an area under the receiver operating characteristic curve of 0.76 ± 0.07 solely based on wearable data. Feature analysis revealed that the ML model associated increased heart rate, decreased heart rate variability, and increased tonic electrodermal activity with hypoglycemia.Our approach may allow for noninvasive hypoglycemia detection using wearables in people with diabetes and thus complement existing methods for hypoglycemia detection and warning.
Gastrointestinal Consequences of Type 2 Diabetes Mellitus and Impaired Glycemic Homeostasis: A Mendelian Randomization Study
Authors: Jie Chen, Shuai Yuan, Tian Fu, Xixian Ruan, Jie Qiao, Xiaoyan Wang, Xue Li, Dipender Gill, Stephen Burgess, Edward L. Giovannucci, Susanna C. Larsson
Journal: Diabetes Care (2023)

We conducted a Mendelian randomization (MR) study to examine the associations of type 2 diabetes and glycemic traits with gastrointestinal diseases (GDs).Uncorrelated genetic variants associated with type 2 diabetes (n = 231), fasting insulin (n = 38), fasting glucose (n = 71), and hemoglobin A1c (n = 75) at the genome-wide significance were selected as instrument variables. Genetic associations with 23 common GDs were obtained from the FinnGen and UK Biobank studies and other large consortia.Genetic liability to type 2 diabetes was associated with the risk of 12 GDs. Per 1-unit increase in the log-transformed odds ratio (OR) of type 2 diabetes, the OR was 1.06 (95% CI, 1.03-1.09) for gastroesophageal reflux disease, 1.12 (95% CI, 1.07-1.17) for gastric ulcer, 1.11 (95% CI, 1.03-1.20) for acute gastritis, 1.07 (95% CI, 1.01-1.13) for chronic gastritis, 1.08 (95% CI, 1.03-1.12) for irritable bowel syndrome, 1.04 (95% CI, 1.01-1.07) for diverticular disease, 1.08 (95% CI, 1.02-1.14) for acute pancreatitis, 1.09 (95% CI, 1.05-1.12) for cholelithiasis, 1.09 (95% CI, 1.05-1.13) for cholelithiasis with cholecystitis, 1.29 (95% CI, 1.17-1.43) for nonalcoholic fatty liver disease, 1.12 (95% CI, 1.03-1.21) for liver cirrhosis, and 0.93 (95% CI, 0.89-0.97) for ulcerative colitis. Genetically predicted higher levels of fasting insulin and glucose were associated with six and one GDs, respectively.Associations were found between genetic liability to type 2 diabetes and an increased risk of a broad range of GDs, highlighting the importance of GD prevention in patients with type 2 diabetes.
A National Physician Survey of Deintensifying Diabetes Medications for Older Adults With Type 2 Diabetes
Authors: Scott J. Pilla, Rabia Jalalzai, Olive Tang, Nancy L. Schoenborn, Cynthia M. Boyd, Sherita H. Golden, Nestoras N. Mathioudakis, Nisa M. Maruthur
Journal: Diabetes Care (2023)

OBJECTIVE To determine physicians’ approach to deintensifying (reducing/stopping) or switching hypoglycemia-causing medications for older adults with type 2 diabetes. RESEARCH DESIGN AND METHODS In this national survey, U.S. physicians in general medicine, geriatrics, or endocrinology reported changes they would make to hypoglycemia-causing medications for older adults in three scenarios: good health, HbA1c of 6.3%; complex health, HbA1c of 7.3%; and poor health, HbA1c of 7.7%. RESULTS There were 445 eligible respondents (response rate 37.5%). In patient scenarios, 48%, 4%, and 20% of physicians deintensified hypoglycemia-causing medications for patients with good, complex, and poor health, respectively. Overall, 17% of physicians switched medications without significant differences by patient health. One-half of physicians selected HbA1c targets below guideline recommendations for older adults with complex or poor health. CONCLUSIONS Most U.S. physicians would not deintensify or switch hypoglycemia-causing medications within guideline-recommended HbA1c targets. Physician preference for lower HbA1c targets than guidelines needs to be addressed to optimize deintensification decisions.
Podocyte-Parietal Epithelial Cell Interdependence in Glomerular Development and Disease
Authors: Robert Bronstein, Jesse Pace, Yogesh Gowthaman, David J. Salant, Sandeep K. Mallipattu
Journal: Journal of the American Society of Nephrology (2023)

Podocytes and parietal epithelial cells (PECs) are among the few principal cell types within the kidney glomerulus, the former serving as a crucial constituent of the kidney filtration barrier and the latter representing a supporting epithelial layer that adorns the inner wall of Bowman's capsule. Podocytes and PECs share a circumscript developmental lineage that only begins to diverge during the S-shaped body stage of nephron formation–occurring immediately before the emergence of the fully mature nephron. These two cell types, therefore, share a highly conserved gene expression program, evidenced by recently discovered intermediate cell types occupying a distinct spatiotemporal gene expression zone between podocytes and PECs. In addition to their homeostatic functions, podocytes and PECs also have roles in kidney pathogenesis. Rapid podocyte loss in diseases, such as rapidly progressive GN and collapsing and cellular subtypes of FSGS, is closely allied with PEC proliferation and migration toward the capillary tuft, resulting in the formation of crescents and pseudocrescents. PECs are thought to contribute to disease progression and severity, and the interdependence between these two cell types during development and in various manifestations of kidney pathology is the primary focus of this review.
Novel Approaches to the Treatment of Chronic Graft-Versus-Host Disease
Authors: Robert Zeiser
Journal: Journal of Clinical Oncology (2023)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology , to patients seen in their own clinical practice. Chronic graft-versus-host disease (cGVHD) is an immune-mediated disease that ensues after allogeneic hematopoietic cell transplantation often affecting multiple organs, decreases quality of life, and necessitates immunosuppressive therapy. The current standard first-line cGVHD therapy is glucocorticoids (GCs) which have major side effects. So far, all attempts to improve response to first-line GC therapy of cGVHD by adding other agents, such as mycophenolate mofetil, or cyclosporine A have not improved response. The data reported in the trial by Miklos et al indicate that ibrutinib should not be added to GC in first-line cGVHD therapy. The findings instruct future studies that aim at the identification of patients with cGVHD who may benefit from a GC-ibrutinib combination using biomarkers or clinical parameters. Currently, ibrutinib, ruxolitinib, and belumosudil are the only drugs that are approved by the Food and Drug Administration for steroid-refractory cGVHD. In light of the current standard management of cGVHD, the trial results indicate that ibrutinib will remain reserved for second-line therapy, which may be due to its mechanisms of action. The recommendation on the basis of this trial is that GC monotherapy remains the standard therapy for cGVHD.
Hematopoietic stem cell aging and leukemia transformation
Authors: Patricia A. Colom Díaz, Jayna J. Mistry, Jennifer J. Trowbridge
Journal: Blood (2023)

With aging, hematopoietic stem cells (HSCs) have an impaired ability to regenerate, differentiate, and produce an entire repertoire of mature blood and immune cells. Owing to dysfunctional hematopoiesis, the incidence of hematologic malignancies increases among elderly individuals. Here, we provide an update on HSC-intrinsic and -extrinsic factors and processes that were recently discovered to contribute to the functional decline of HSCs during aging. In addition, we discuss the targets and timing of intervention approaches to maintain HSC function during aging and the extent to which these same targets may prevent or delay transformation to hematologic malignancies.